17beta-(lower cycloalk-1&#39;-enyloxy) and 17beta-(1&#39;-lower alkoxy-lower cycloalkoxy) derivatives of 2-cyano-delta2-androsten-17beta-ol



United States Patent 17fi-(LOWER CYCLOALK-1-ENYLOXY) AND 175- (1'-LOWER ALKOXY-LOWER CYCLOALKOXY) DERIVATIVES 0F Z-CYANO-M-ANDROSTEN- 17B-0L Albert Bowers and Pierre Crabbe, Mexico City, Mexico, assignors to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed June 17, 1963, Ser. No. 288,443

9 Claims. (Cl. 260-3975) s A2 a2 1'33 B3 Vi I \/i II In these formulas, the grouping r tz B3 or the grouping wherein R represents a lower alkyl group, e.g., methyl,

ethyl, propyl and the like; at the 2,3-position of the steroid nucleus, the carbon and hydrogen atoms normally present at these positions being omitted in the aboveillustrations for the sake of clarity; R represents a lower alkyl group, and Z represents, a divalent hydrocarbon chain of up to 6 carbon atoms, e.g., propylene, i.e.,

Ii,l88,327 Patented June 8, 1965 "ice ' The novel compounds of the present invention can be prepared by the process depicted by the following reaction scheme:

In these formulas R and Z have the same meanings as set forth hereinabove.

In practicing the process depicted above, the starting material (Ill), either a Zea-lower alkyl dihydrotestosterone, e.g., 2a-metl1yldihydrotestosterone, or 2-cyano-A -androsten-l7,B-ol, is reacted with a di('lo,Wer alkyl)ketal of a lower cycloalkanone, wherein the lower cycloalkanone moiety contains up to 8 carbon atoms, such as the dimethyl ketal of cyclopentanone, the diethyl ketal of cyclo pentanone, the diethyl ketal of cyclohexanone, the dipropyl ketal of cyclohexanone, the diethyl ketal of cyclo heptanone, and the like, to give the corresponding 17;?- (lower cycloalk-l-enyloxy) derivative (I) and/ or the corresponding l7,8-(1-lower alkoxy-lower cycloalkoxy) derivative (II).

This reaction can be effected either in the presence of an inert organic solvent, e.g., an aromatic hydrocarbon such as benzene, toluene, Xylene, and the like, or a halogenated aliphatic hydrocarbon such as methylene chloride, chloroform, and the like, or in the absence or" any solvent. Similarly, an acid catalyst, e.g., a hydrocarbon sulfonic acid such as p-toluenesulfonic acid and the like, can be employed if desired but is not essential.

The reaction will usually be carried out at reflux temperature for periods of time ranging from about 15 minutes to about 12 hours, with the longer of these reaction times, especially in the presence of a solvent and an acid catalyst, generally favoring the formation of the 17;?- (lower cycloalk-l'-enyloxy) derivatives. However, longer or shorter reaction times coupled with lower or higher reaction temperatures can be employed, if desired, and thus the choice of any particular set of operating conditions is not critical, and will be determined in large measure by the types and amounts of products desired.

The following working examples serve to illustrate, but are not intended to limit the scope of the present invention:

Example I A mixture of 1 g. of 2a-methyl-dihydro-testosterone,

400 cc. of chloroform and 20 mg. of p-toluenesulfonic acid, was heated till 20 cc. of chloroform distilled off, in order to remove moisture. Then there were added 5 cc. of the diethyl ketal of cyclopentanone and the distillation was continued for 0.5 hour. Pyridine was added, the solvents evaporated and the residue crystallized from acetone-hexane, thus furnishing 17,8-(1-ethoxy cyclopentyloxy)-2-a-methy1-androstan-3-0ne (Compound No. 1).

Example II 2u-methyl-dihydrotestosterone was treated following the procedure described in Example I, except that the dimethyl ketal of cyclopentanone was used instead of the diethylketal, thus giving 17B-(1'-methoxycylopentyloxy)- 2a-methy1androstan-3-one (Cpd. No. 2).

Example III Example V 2-cyano-A -androsten-17,8-01 (obtained from the corresponding 2-formyl compound by conventional procedures via the oxime thereof) was treated according to Examples V I, II, III and IV, thus affording respectively: Cpd. No.:

5. 175-(1'-eth0xycyclopentyloxy)-2-cyan0 A androstene, 6. 17fi-(1'-methoxycyc1opentyloxy)-2-cyano-A3 androstene, 7. 17/5'-(1-ethoxycyclohexyloxy)-2-cyano-A androstene, 8. 17fi-(1-ethoxycyc1oheptyloxy)-2-cyano A androstene,

Example VI A mixture of 1 g. of 2a-methyl dihydro testosterone, 200 cc. of benzene and 20 mg. of p-toluenesulfonic acid was heated till 30 cc. of benzene distilled off. Thereafter 5 cc. of the diethylketal of cyclopentanone were added and the resulting solution was refluxed for 8 hours. Pyridine was added, the solvents removed and the residue crystallized from acetone-hexane, thus yielding 17B-(cyclpent-1'-enyl0xy)-2a-methyl-androstan-3-one (Cpd. NO. 9).

Example VII Za-methyl dihydrotestosterone was treated according to Example VI, except that the diethylketal of cyclopentanone was substituted by the diethylketal of cyclohexanone and by the diethyl-ketal of cycloheptanone, thus furnishing respectively 17 8-(cyclohex-1-enyloxy) 2amethyl-androstan-3-one (Cpd. No. 10) and 17p-(cyclohept-1'-enyloxy)-2a-methyl-androstan-3 one (Cpd. N0. 11).

Example VIII 2-cyano-A -androsten-17,8-01 was treated in accordance i with Examples VI and VII, thus yielding respectively: Cpd. No.:

12. 17/3-cyclopent-1'-enyloxy)-2-cyano A androstene, 13. 17B-(cyclohex-1-enyloxy)-2-cyano A androstene 14. 17B-(cyclohept-1'-enyloxy)-2-cyano A andro stene.

Example IX A mixture of 1 g. of 2a-rnethyl-dihydrotestosterone and 5 cc. of the diethylketal of cyclopentanone was refluxed for 5 hours, and then evaporated to dryness. The residue was chromatographed on alumina, thus affording 17/3-(1'- ethoxycyclopentyloxy)-2a-methyl-androstan-3 one (Cpd. No. 1) and 17p-(cyclopent-l'-enyloxy)-2-a-methyl-andr0- stan-3-one (Cpd. N0. 9).

We claim:

1. A compound represented by the formula:

2. 17/3-cyclopent-1'-enyloxy)-2-cyano-A -androstene. 3. 17B- (cyclohex- 1 '-enyloxy) -2-cyan0-A -androstene. 4. 17B-(cyclohept-1'-enyloxy)-2-cyano-A -androstene. wherein Z is a divalent hydrocarbon chain of up to 6 carbon atoms.

5. A compound represented by the formula:

I OR

j wherein R is a lower alkyl group and Z is a divalent hydrocarbon chain of up to 6 carbon atoms.

6. 17B-(1'-methoxycyclopentyloxy)-2-cyano-A andro- 'li 17;6-(1'-ethoxycyclopentyloxy)-2-cyano-A3 andro- 3 17,641'-ethoxycyclohexyloxy)-2-cyano A andror 17fi-(1-ethoxycycloheptyloxy)-2-cyano-A andros ene.

References Cited by the Examiner Ercoli et al., Chem. and Ind., p. 128445, July 1962. Fieser et al., Steroids 1959), p. 692-96, Reinhold Pub. Co., NY.

LEWIS GOTTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,188,327 June 8, 1965 Albert Bowers et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 4, after the formula in claim 1, insert the following:

wherein Z is a divalent hydrocarbon chain of up to 6 carbon atoms.

Signed and sealed this 19th day of October 1965.

(SEAL) Allest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND REPRESENTED BY THE FORMULA: 